Combined diffusion/osmotic pumping drug delivery system

ABSTRACT

Delivery devices capable of delivering one or more active substances by diffusion through plural micropores in the membrane ( 4 ) or by osmotic pumping through one or more preformed passageways ( 5 ) in the membrane are provided. The device ( 1 ) has an about centrally located expandable core ( 2 ) completely surrounded by an active substance-containing layer ( 3 ), which is completely surrounded by the membrane. The device is capable of delivering insoluble, slightly soluble, sparingly soluble and very soluble active substances to an environment of use. The preferred delivery rate is zero order. The device can deliver an active substance for a period of about 12-24 hours.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

The present application is a continuation-in-part of application Ser.No. 09/483,282 filed Jan. 14, 2000 now U.S Pat. No. 6,352,721.

FIELD OF THE INVENTION

This invention pertains to a delivery device for the controlled releaseof active agents to an environment of use. More particularly, theinvention pertains to a device for the delivery of active agents over aprolonged and extended period of time. The controlled delivery devicecomprises an expandable-hydrophilic polymer-core located substantiallyin the center of the dosage form surrounded by a composition of theactive agent(s) to be delivered. A novel dual function membrane permitsdelivery of the active agent(s) through a combination of diffusion andosmotic pumping mechanisms.

BACKGROUND OF THE INVENTION

Osmotic devices have demonstrated utility in delivering beneficialactive agents, such as medicines, nutrients, food, pesticides,herbicides, germicides, algaecides, chemical reagents, and others, to anenvironment of use in a controlled manner over prolonged periods oftime. Known devices include tablets, pills, and capsules.

Several advancements have been made in the art to improve the deliveryof insoluble or slightly soluble products to an environment of use. Theprior art has focused on the development of new membranes that deliveractive agents by diffusion and/or osmotic pumping.

U.S. Pat. No. 4,235,236 to Theeuwes discloses an osmotic device thatdelivers drug by the combined mechanisms of diffusion and osmoticpumping. The device comprises a microporous wall surrounding acompartment containing an active agent and an expandable member. Theexpandable member consists of a semipermeable, flexible or expandablefilm surrounding a member selected from the group consisting of anosmotically effective solute, a gas generating couple and a swellablepolymer. The external wall of the device is formed of a microporousmaterial through which the active agent is delivered. This patent doesnot disclose the inclusion of a passageway in the external wall toprovide delivery by osmotic pumping and diffusion. Even though thesolution proposed by U.S. Pat. No. 4,235,236 allows the release of anactive agent at a steady rate—the so called zero-order release—, itrequires the manufacturing of an elastic film that separates theexpandable member from the composition comprising the active agent. Theadhesion process between said membrane and said composition comprisingthe active agent requires complicated processing steps that make theformulation very expensive.

U.S. Pat. No. 4,327,725 to Cortese and Theeuwes, discloses an osmoticdevice comprising a semipermeable wall surrounding two layers, one layercontaining an active agent and the other an expandable hydrogel. Apassageway in the wall communicates the active agent layer with theenvironment of use. The patent describes the use of cellulose acylate asthe material comprising the semipermeable membrane.

U.S. Pat. Nos. 5,612,059 and 5,698,220 to Cardinal et al., disclose theuse of asymmetric membranes in delivery devices. These membranes may bepermeable, semipermeable, perforated or unperforated and can deliver anactive substance by the combined mechanisms of diffusion and osmoticpumping. These patents also disclose the formation of asymmetricmembranes with 398-10 (Eastman) cellulose acetate.

EP 636366 and EP 553392 disclose an active agent composition coated withan aqueous dispersion of plasticized acrylic polymer, which is subjectedto a particular curing process. The controlled release formulationdisclosed in these applications has a stable dissolution profile despiteexposure to a variety of storage conditions.

U.S. Pat. No. 5,543,155 to Fekete et al. discloses a controlled deliverypharmaceutical composition core surrounded by a wall comprising anammonium methacrylate copolymer that is permeable to low molecularweight (MW) molecules. This controlled delivery pharmaceuticalcomposition contains an active pharmaceutical compound and hydroxypropylmethylcellulose (HPMC) as the hydrophilic polymer. Low MW osmagents arenot incorporated into the composition. Tablets having a bi-layered coreare prepared with a hydrophilic polymer layer comprising high molecularweight HPMC, which has a viscosity higher than 1000 cP in a 2% aqueoussolution.

U.S. Pat. No. 5,543,155 also discloses various combinations of Eudragit™RL (easily permeable films) and Eudragit™ RS (not easily permeablefilms). The use of a permeable membrane alone, however, does not allowthe inclusion of a low molecular weight osmotic agent in thepharmaceutical composition tablet core (for example, potassium chloride,sodium tartrate, sodium chloride, sodium sulfate, etc.). Thus, it limitsthe versatility of the device to the delivery of active agents thatrequire a significant absorption of liquid to achieve an effective andconstant delivery of solution or suspension of the active agent from thedevice. Osmotic devices having a bi-layered core, one layer containingthe active agent and the other being a swellable placebo layer,surrounded by a semipermeable membrane possess significantdisadvantages. The placebo layer consists mainly of a swellable polymerand/or a hydrogel that, while absorbing fluid from the environment ofuse, expands and exerts pressure over the layer that contains the activeagent thereby releasing the active agent through a passageway in thewall. The prior art teaches that perforation of the semipermeablemembrane needs to be carried out selectively on the side of the membranethat is adjacent to the layer comprising the active agent. In fact, ifthe membrane is perforated adjacent the placebo layer, the active agentwill not be released. If two perforations are carried out, one adjacentthe active-agent layer and the other adjacent the swellable polymerlayer (“push” layer), both the active agent and the swellable polymerare released, resulting in loss of the “push” effect. The device wouldtherefore act as a simple osmotic pump that would not allow the releaseof the entire charge of active agent in the dosage form. The preciseselection of which portion of the membrane should be drilled requiresthe use of color or shape coding in order to distinguish the layers, aswell as meticulous handling of the devices. The handling of the devicesrequires the use of sophisticated and expensive electronic equipmentable to recognize the different layers of the tablet core.

U.S. Pat. No. 5,543,155 also discloses perforation of the membraneadjacent both layers of the core; however, a specific high molecularweight polymer (HPMC) is required to prevent the loss of the push layerleaving a significant number of available hydrophilic polymersunavailable for use in these devices.

U.S. Pat. No. 5,516,527 to Curatolo discloses a device that can includea preformed passageway and plural pores. The device requires theformation of a phase-separated coating that ultimately forms a porousmembrane.

While the prior art discloses a wide variety of osmotic devices, nosingle device has been found to be generally applicable and, in fact,most known devices are designed to operate within a relatively narrowrange of conditions. For example, a first formulation of an osmoticdevice may be generally useful for delivering slightly to sparinglywater soluble components to an environment of use, but that sameformulation will require drastic changes in order to deliver a verywater soluble component and vice versa. In addition, diffusioncontrolled devices are generally useful for delivering sparingly tovery, but not slightly, water soluble components to an environment ofuse. Therefore, a need remains for a delivery device capable ofdelivering components having very different solubilities to anenvironment of use without requiring a dramatic reformulation of thedevice.

SUMMARY OF THE INVENTION

The present invention provides a controlled release device for activesubstances comprising an external dual delivery membrane having at leastone preformed passageway and plural micropores, wherein the devicereleases the active agent through a combination of diffusion and osmoticpumping. The at least one passageway can be located anywhere in the dualdelivery membrane.

The present invention also provides a controlled release device havingan approximately centrally located core comprising a hydrophilicexpandable polymer and, optionally, an osmagent, wherein the core issurrounded by a composition comprising at least one active agent andpreferably an osmagent and/or an osmopolymer. During operation in anenvironment of use, the hydrophilic core imbibes fluid and increases involume thereby forcing release of the active agent(s) through either thepores of the membrane by diffusion and/or the passageway by osmoticpumping effect.

The invention also provides a therapeutic device for the delivery ofpharmaceutically active agents, ranging in solubility from slightlysoluble to very soluble drugs, in a controlled, continuous andapproximately steady, preferably zero order, rate over a prolongedperiod of time.

The invention also provides a smaller than usual dosage form thatdelivers active compounds by diffusion through the entire surface of thedevice. In this way, a portion of the membrane that releases activecompounds is doubled with respect to conventional bi-layered devices.

The invention also provides a controlled release device containing ahigh or low molecular weight osmagent inside the core of the device,thereby enabling the device to absorb greater quantities of fluid,deliver a greater range of active agents irrespective of theirsolubility, and deliver the active agents by diffusion and/or osmoticpumping.

The device of the present invention may optionally be provided with anexternal coating comprising one or more active agents for immediatedelivery to the environment of use.

Accordingly, one aspect of the present invention provides an improveddevice for the controlled delivery of active agents to an environment ofuse, wherein the device comprises:

a) a core located approximately at the center of the device andcomprising at least one expandable hydrophilic polymer and optionally anosmagent, the core being able to absorb and/or imbibe fluids from oneenvironment of use;

b) a composition immediately surrounding the core comprising at leastone active substance and, optionally, an osmagent and/or an osmopolymer;

c) a membrane immediately surrounding the composition and comprising amixture of a cellulose acylate (ester), a methacrylate salt copolymerand a plasticizer, wherein the membrane permits delivery of the at leastone active substance through a combination of diffusion and osmoticpumping; and

d) at least one preformed passageway and plural micropores in themembrane that communicate the composition with the outside of thedevice.

Another aspect of the invention provides a device for the controlleddelivery of at least one active agent to an environment of use, whereinthe device comprises:

a core expandable in a fluid from the environment of use, the core beingapproximately centrally located in the device;

a layer comprising at least one first active agent, wherein the layer isin contact with and surrounds the core; and

a membrane in contact with and surrounding the layer and comprising atleast one preformed passageway for delivery of the at least one activeagent by osmotic pumping and plural micropores for delivery of the atleast one active agent by diffusion, and the membrane further comprisingone or more cellulose esters, one or more poly(methacrylate) copolymersalts and one or more plasticizers,

wherein the membrane permits delivery of the at least one activesubstance through a combination of diffusion and osmotic pumping.

Specific embodiments of the invention include those wherein: 1) thedevice further comprises a drug-containing coat external to themembrane, wherein the drug-containing coat comprises a second activeagent, provides an immediate, rapid, controlled and/or delayed releaseof the second active agent and the external coat surrounds at least aportion of the membrane; 2) the first and second active agents aredifferent and are independently selected at each occurrence from thegroup consisting of an antibiotic agent, antihistamine agent,decongestant, anti-inflammatory agent, antiparasitic agent, antiviralagent, local anesthetic, antifungal agent, amoebicidal agent,trichomonocidal agent, analgesic agent, anti-arthritic agent,anti-asthmatic agent, anticoagulant agent, anticonvulsant agent,antidepressant agent, antidiabetic agent, antineoplastic agent,anti-psychotic agent, neuroleptic agent, antihypertensive agent,hypnotic agent, sedative agent, anxiolytic energizer agent,antiparkinson agent, muscle relaxant agent, antimalarial agent, hormonalagent, contraceptive agent, sympathomimetic agent, hypoglycemic agent,antilipemic agent, ophthalmic agent, electrolytic agent, diagnosticagent, prokinetic agent, gastric acid secretion inhibitor agent,anti-ulcerant agent, anti-flatulent agent, anti-incontinence agent, andcardiovascular agent; 3) the first active agent is a prokinetic agentand the second active agent is a gastric acid secretion inhibitor agent;4) the first active agent is a decongestant and the second active agentis an antihistamine; 5) the first active agent is a firstanti-incontinence agent and the second active agent is a differentsecond anti-incontinence agent; 6) the anti-incontinence agents areselected from the group consisting of oxybutynin, tolterodine anddarifenacin; 7) the first active agent is a first antihypertensive agentand the second active agent is a different second antihypertensiveagent; 8) the antihypertensive agents are selected from the groupconsisting of a calcium channel blocker agent, an angiotensin convertingenzyme inhibitor agent, a diuretic agent and a beta-adrenergicantagonist agent; 9) the first active agent is an antidepressant agentand the second active agent is an anti-psychotic agent; 10) the firstactive agent is a first analgesic or, anti-inflammatory agent and thesecond active agent is a different second analgesic or,anti-inflammatory agent; 11) the analgesic and anti-inflammatory agentsare selected from the group consisting of an non-steroidalanti-inflammatory agent, a steroidal anti-inflammatory agent, an opioidreceptor agonist agent, and a selective or specific COX-II inhibitoragent; 12) the first active agent is an antiviral agent and the secondactive agent is an antihistamine agent; 13) the first active agent is amuscle relaxant agent and the second active agent is ananti-inflammatory or analgesic agent; 14) the first active agent ispridinol and the second active agent is a selective or specific COX-IIinhibitor agent; 15) the first and second active agents are the same;16) the membrane comprises about 1 to 99 weight percent of one or morecellulose esters, about 84 to 0.5 weight percent of one or morepoly(methacrylate) copolymer salts and about 15 to 0.5 weight percent ofone or more plasticizers; 17) the cellulose ester is selected form thegroup consisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulose triacetateand combinations thereof; 18) the poly(methacrylate) copolymer salt ispoly(ammonium methacrylate) copolymer; 19) the layer further comprisesat least one of an osmagent and an osmopolymer; the expandable corefurther comprises at least one expandable hydrophilic polymer and,optionally, an osmagent; 20) the expandable hydrophilic polymer is oneor more of hydroxypropyl methylcellulose, alkylcellulose,hydroxyalkylcellulose, poly(alkylene oxide), and combinations thereof;and the at least one cellulose ester is independently selected from thegroup consisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulose triacetateand combinations thereof; 21) the core excludes an active agent; 22) themembrane comprises a mixture of a cellulose acylate, apoly(methacrylate) copolymer salt and a plasticizer; 23) a slightlysoluble or insoluble active substance is delivered predominantly throughthe at least one passageway and a soluble or sparingly soluble activesubstance is delivered predominantly through the plural micropores;and/or 24) the active substance is delivered at an approximately zeroorder rate.

Active agents can include compounds such as biologically orpharmacologically active agents, medicines, nutrients, food products,insecticides, pesticides, herbicides, germicides, algaecides,fungicides, chemical reagents, growth regulating substances,parasiticides, sex sterilants, fertility promoters, biocides,rodenticides, disinfectants, anti-oxidants, plant growth promoters,preservatives, fermentation agents, fertility inhibitors, deodorants,micro-organism attenuators, catalysts, food supplements, cosmetics,vitamins, and other agents that benefit the environment of use.

Preferred embodiments of the invention include those wherein the activesubstance is pharmacologically or biologically active or wherein theenvironment of use is the GI tract of a mammal.

Other preferred embodiments of the device of the invention are used inbiological environments including the oral, ocular, nasal, vaginal,glandular, gastrointestinal tract, rectal, cervical, intrauterine,arterial, venous, otic, sublingual, dermal, epidermal, subdermal,implant, buccal, bioadhesive, mucosal and other similar environments.Likewise, it may be used in aquariums, industrial warehouses, laboratoryfacilities, hospitals, chemical reactions and other facilities.

Other features, advantages and embodiments of the invention will becomeapparent to those of ordinary skill in the art by the followingdescription, accompanying examples and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are given by way of illustration only, and thusare not intended to limit the scope of the present invention. Thedrawings are not drawn to scale.

FIG. 1-a is a sectional view of an oral device according to the presentinvention.

FIG. 1-b is a sectional view of the device of FIG. 1-a, wherein the corehas been expanded by imbibing a fluid.

FIGS. 2 to 4 depict active agent release diagrams using the devices ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1-a depicts an oral dosage form device (1) comprising anapproximately centrally located core (2) comprising an expandablehydrophilic polymer composition capable of absorbing, or imbibing,fluids. The core (2) is surrounded by and in contact with a layer (3),which comprises at least one active agent and optionally an osmoticallyeffective solute. The layer (3) is surrounded by and in contact with awall (4) having pores (not shown) and a preformed passageway (5). Thedevice delivers the active gent by diffusion and osmotic pumping. Thewall (4) is preferably physiologically inert and preserves its physicaland chemical integrity during delivery of the active agents comprised inthe layer (3).

The beneficial agent(s) comprised in the layer (3) is delivered from thedelivery device (1) generally as follows. Fluid is imbibed from anenvironment through the membrane (4) into the device (1). The fluid thenpermeates the layer (3). The hydrophilic core (2) imbibes the fluid andswells pushing the aqueous solution or suspension formed from the layer(3) towards the membrane (4). The beneficial agent is released from thedosage form by molecular diffusion across the membrane (4) and/or byosmotic pumping through the passageway (5) in the membrane.

FIG. 1-b depicts the device of FIG. 1-a in operation delivering theactive agent in the layer (3). During operation, the hydrophilic polymercomposition of the core (2) absorbs fluid that enters the device (1)across the wall (4) and swells, or expands. FIG. 1-b depicts theenlarged core pushing the active agent through the wall and passageway.

The layer preferably completely surrounds the expandable core, therebypromoting isotropic diffusion and thus providing an about zero orderrelease profile.

The inclusion of an about centrally located expandable hydrophilicpolymer core in the present delivery device allows delivery of theactive agent by isotropic diffusion, thus providing a steady releaserate, that is about zero order release profile. The isotropic diffusionprocess provides a release profile closer to the desired zero orderrelease profile while anisotropic diffusion provides a release profilewith an accelerated initial release.

The portion of active agent that is delivered by diffusion or osmoticpumping generally depends upon the diffusivity of the active agentthrough the wall (4) and/or the solubility of the active agent. When thebeneficial agent is poorly soluble in water and has a low diffusivity,the aqueous suspension of the active agent composition of layer (3) ismainly released to the environment of use across the at least onepassageway (5) of the wall in a controlled manner over a prolongedperiod of time. In the case of water soluble active agents, the increasein concentration of the active agent in the solution adjacent themembrane (4) will effect release of the active agent by diffusion.Additionally, the swelling of the expandable hydrophilic polymer corecontributes to the complete release of the solution at a substantiallysteady rate, minimizing diffusional resistance of the boundary layer.

As used herein, the terms “very soluble”, “freely soluble”, “soluble”,“sparingly soluble”, “slightly soluble”, “very slightly soluble”, and“practically insoluble” or “insoluble” are defined as they are definedin the U.S.P. 23^(rd) Ed. as follows:

Solubility of component in water Term (parts of solvent per part ofcomponent) Very soluble <1 Freely soluble  1-10 Soluble 10-30 Sparinglysoluble  30-100 Slightly soluble   100-1,000 Very slightly soluble 1,000-10,000 Practically insoluble or insoluble Over 10,000

The formulation of the present delivery device can be changed accordingto the following guidelines to permit delivery of slightly, sparinglyand very soluble active agents. The following guidelines are applicableto embodiments of the delivery device intended for use in an aqueousenvironment.

For slightly water soluble active agents, such as allopurinol,amoxicilin, aspirin, cefazolin, cimetidine, hydrochlorothiazide,nifedipine, and cisapride monohydrate, the active agent is mostlydelivered through the preformed passageway. The core can comprise anexpandable hydrophilic polymer, such as HPMC, methylcellulose (MC),carboxymethylcellulose sodium (CMC—Na), and poly(alkylene oxides),and/or an osmagent, such as NaCl, mannitol, dextrose, sodium tartrate,and sodium acetate. The layer surrounding and in contact with the corecan comprise the active substance, an osmopolymer, and an osmagent. Thewall surrounding and in contact with the layer containing active agentcan comprise a cellulose ester, such as cellulose acetate, cellulosepropionate, and cellulose acetate-butyrate, a polymethacrylatecopolymer, such as poly(ammonium methacrylate) copolymer and (ethylacrylate)-(methyl methacrylate)-[(trimethylammonium)ethyl methacrylate],and a plasticizer, such as PEG 400, PEG 6000, triacetin and glycerin.The cellulose ester, polymethacrylate copolymer and plasticizer aregenerally present in the ratio of 0.1-99.8 wt. cellulose ester:0.1-99.8% wt. polymethacrylate copolymer: 0.1-25% plasticizer. For verywater soluble active agents, such as meperidine HCl, buspirone HCl,diltiazem HCl, oxybutynin HCl, ranitidine HCl, pseudoephedrine HCl, andvenlafaxine HCl, the active agent is delivered through both thepreformed passageway and the micropores of the wall. The core cancomprise a hydrophilic expandable polymer and an osmagent. The layersurrounding and in contact with the core can comprise the activesubstance, and a hydrophilic expandable polymer and an osmagent. Thewall surrounding and in contact with the layer containing activesubstance generally comprise a cellulose ester, a poly(methacrylate)copolymer, and a plasticizer.

For sparingly water soluble active substances, such as caffeine,ciprofloxacin HCl, enalapril maleate, and metronidazole, the activeagent is delivered through both the preformed passageway and themicropores of the wall. The core can comprise an expandable hydrophilicpolymer, and an osmagent, such as. The layer surrounding and in contactwith the core can comprise the active substance, an osmopolymer and anosmagent. The wall surrounding and in contact with the layer containingactive agent can comprise a cellulose ester, a polymethacrylatecopolymer, and a plasticizer. The cellulose ester, polymethacrylatecopolymer and plasticizer are generally present in the ratio of0.1-99.8% wt. cellulose ester: 0.1-99.8% wt. polymethacrylate copolymer:0.1-25% plasticizer.

The micropores in the wall are not formed by mechanical means. Themicropores are formed during preparation of the wall or during exposureto fluids in an intended environment of use. Methods of preparing wallswherein the micropores form in the environment of use are well known anddescribed in, among others, U.S. Pat. Nos. 3,845,770, 3,916,899,4,063,064, 4,088,864, 4,816,263, 4,200,098, 4,285,987 and No. 5,912,268,the relevant disclosures of which are hereby incorporated by reference.

Swellable hydrophilic polymers suitable for manufacturing the core (2)include hydrophilic polymers that interact with water and/or aqueousbiological fluids, and swell and retain water within their structure.The core preferably expands to about 2 to 50 times its initial volume.The polymers are preferably slightly cross-linked. Uncross-linkedpolymers will preferably not dissolve in water, keeping their physicalintegrity. The polymers are of animal, plant or synthetic origin.Hydrophilic polymers suitable for manufacturing the core of theinvention preferably include hydroxypropyl methylcelluloses (viscosityfrom 3 to 100,000 cps, measured in 2% w/v solution); ethylcelluloses(viscosity from 3 to 110 cP, measured in 5% w/v solution);methylcelluloses (viscosity from 10 to 10,000 cP, measured in 2% w/vsolution); hydroxypropylcelluloses (general average molecular weight ofabout 80,000 to 1,150,000); hydroxyethylcelluloses (viscosity from 2 to21,000 cP, measured in 2% w/v solution); carboxymethylcelluloses(viscosity from 5 to 4,000 cP, measured in 1% w/v solution); poly(alkylene) oxide that might include homopolymer of ethylene oxide,propylene oxide and butylene oxide and copolymers of those.

The poly(alkylene oxides) used herein preferably have an averagemolecular weight of about 1,000,000 to 2,000,000 (viscosity around400-800 and 2,000-4,000 cP, measured in 2% w/v solution), or an averagemolecular weight around 4,000,000 to 8,000,000 (viscosity around1,650-5,500 and 10,000-15,000 cP, measured in 1% w/v solution).

The membrane, or wall, (4) according to the invention preferablycomprises a mixture of cellulose esters (CE), copolymers of methacrylatesalts (CM) and a plasticizer (P). The active agent is released in acontrolled manner through the membrane (4) by the combined mechanisms ofdiffusion and osmotic pumping. The ratio CE:CM:P is preferably about1-99% of CE: about 84-0.5% of CM weight: about 15-0.5% of P by weight.The ratio of these ingredients is varied to control delivery of activeagents either predominantly by diffusion across the surface of themembrane (4) to predominantly by osmotic pumping through the passageway(5) and combinations thereof.

Representative cellulose esters useful in the membrane of the inventioninclude cellulose acylate; mono, di and tricellulose alkanylates; mono,di and tricellulose aroylates; cellulose propionate; celluloseacetate-butyrate; cellulose triacylates such as cellulose trivalerate,cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate;cellulose diacylates such as cellulose disuccinate, cellulosedipalmitate; combinations thereof and other cellulose esters used bythose of ordinary skill in the art in the preparation of controlleddelivery devices and membranes.

The poly(methacrylate) copolymer salts used in the manufacturing of themembrane (4) are preferably insoluble in water and in digestive fluids,but films made therefrom are preferably permeable to dissolvedsubstances to different degrees. Preferred copolymers include:poly(ammonium methacrylate) copolymer RL (Eudragit™ RL), poly(ammoniummethacrylate) copolymer (type A-USP/NF), poly(aminoalkyl methacrylate)copolymer RL-JSP I), and (ethyl acrylate)-(methylmethacrylate)-[(trimethylammonium)-ethylmethacrylate] (1:2:0.2)copolymer, MW 150,000. More preferred polymers include (Röhm Pharma,Weiterstadt): Eudragit™ RS 100: solid polymer, Eudragit™ RL 12.5:12.5%solution in solvent, Eudragit™ RL 30 D: 30% aqueous dispersion, andother equivalent products.

The following poly (ammonium methacrylate) copolymers can also be used:ammonium methacrylate copolymer RS (Eudragit™ RS), poly(ammoniummethacrylate) copolymer (type B-USP/NF), poly(aminoalkyl methacrylate)copolymer (RSL-JSP I), (ethyl acrylate)-(methylmethacrylate)-[(trimethylammonium)-ethyl methacrylate] (1:2:0.1)copolymer, PM 150,000. Specific polymers include (Röhm Pharma,Weiterstadt): Eudragit™ RS 100: solid polymer, Eudragit™ RS 12.5: 12.5%solution in solvent, Eudragit™ RS 30 D: 30% aqueous dispersion and otherequivalent products. Eudragit™ RL is readily water permeable whileEudragit™ RS is hardly water permeable. By employing mixtures of bothEudragit™ RL and Eudragit™ RS, membranes having the desired degree ofpermeability are prepared.

The porosity of the wall will vary according to its composition. Ahighly porous wall is preferably used to deliver slightly soluble activesubstances. A highly porous wall will provide a faster release of drugthan a slightly porous wall. A slightly porous wall is generally used todeliver very soluble active substances. A moderately porous wall isgenerally used to deliver moderately soluble active substances. Amoderately porous wall will provide a faster release of drug than aslightly porous wall.

Plasticizers that can be used in the membrane of the invention includeall those that are generally incorporated into polymeric coatings ofdelivery devices. Plasticizers generally improve the mechanicalproperties and increase the flexibility of the polymeric film.Plasticizers generally reduce cohesive intermolecular forces andincrease mobility of polymer chains, thus reducing polymer-polymerinteractions. This action is responsible for the changes to theproperties of the polymers and films thereof such as a reduction of Tg(glass transition temperature) or softening temperature and the elasticmodule, increasing polymer flexibility, thus facilitating the process offormation of the membrane or film. A preferred pharmaceuticalplasticizer is non-toxic and non-irritating; has a reduced tendency tomigrate, extrude or volatilize; and has good miscibility with thepolymers in film. Plasticizers that are used in the wall of the presentinvention include, for example, acetyl triethyl citrate, acetyl tributylcitrate, triethyl citrate, acetylated monoglycerides, glycerol,polyethylene glycol, triacetin, propylene glycol, dibutyl phthalate,diethyl phthalate, isopropyl phthalate, dimethyl phthalate, dactylphthalate, dibutyl sebacate, dimethyl sebacate, castor oil, glycerolmonostearate, fractionated coconut oil, and others. Preferably,polyethylene glycol is used, for example PEG 400, which is availablefrom suppliers such as Aldrich, Sigma Chemical Co. and others.

Suitable plasticizers also include, by way of example and withoutlimitation, low molecular weight polymers, oligomers, copolymers, oils,small organic molecules, low molecular weight polyols having aliphatichydroxyls, ester-type plasticizers, glycol esters, poly(propyleneglycol), multi-block polymers, single-block polymers, low molecularweight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin. Such plasticizers can alsoinclude ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, diethylene glycol, triethylene glycol, tetraethyleneglycol and other poly(ethylene glycol) compounds, monopropylene glycolmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate and allyl glycolate. All such plasticizers arecommercially available from sources such as Aldrich or Sigma ChemicalCo. A combination of plasticizers may also be used in the presentformulation. The PEG based plasticizers are commercially available orcan be made by a variety of methods, such as disclosed in Poly (ethyleneglycol) Chemistry: Biotechnical and Biomedical Applications (J. M.Harris, Ed.; Plenum Press, NY) the disclosure of which is herebyincorporated by reference.

The passageway (5) in the membrane (4) that connects the inside of thedelivery device (1) with the outside allows release of the active agentto the environment of use. Exemplary passageways include an orifice,hole, bore, aperture or the like, through which the active agent isreleased. Mechanical perforation, laser perforation or any other methodknown to the artisan of ordinary skill in the art is used to form thepassageway. Although the osmotic device (1) is depicted with a singlepassageway (5), a device according to the present invention can compriseone or more passageways including two, three, four, five, six, seven,eight, nine, ten or more passageways. The one or more passageway/s areformed in any place of the delivery device. The maximum and minimumdimensions of the passageway are preferably as disclosed in U.S. Pat.No. 3,845,770 (AR 199,301).

The device of the present invention can, optionally, include an externalcoating comprising an active agent for immediate, rapid, slow,sustained, extended, controlled or delayed delivery to the environmentof use. Useful materials for the external coating includepoly(vinylpyrrolidone) (PVP), poly(ethylene glycol) (PEG), hydroxypropylethylcellulose, hydroxypropyl methylcellulose, ethylcellulose,hydroxyethylcellulose, sodium carboxymethyl cellulose,dimethylaminoethyl methalcrylate-methalcrylate acid ester copolymer,soluble polysaccharide gums such as carrageenan, tragacanth, pectin,guar, combinations thereof and other such materials known by those ofordinary skill in the art. The external layer is dissolved, eroded orcompletely removed in the environment of use and provides an immediatedelivery of the active agent to the environment of use. The active agentcomprises about 0.1 to 99.9% by weight of the external coating.

The layer (3) depicted in FIG. 1-a includes a composition comprising anactive agent and optionally other materials as discussed herein. Thequantity of active agent may vary between 0.10 and 99.9% by weight ofthe layer (3). The preferred amount of active agent in the layer (3) mayvary according to the active agent employed.

Osmotically effective compounds, such as osmotic agents or osmagents,that are capable of being totally or partially solubilized in the fluidmay be added to the layer (3). Osmagents or osmotically effectivecompounds are generally soluble in the fluid that enters into the devicethrough the wall (4) creating an osmotic pressure gradient across thewall. The fluid and components of the layer (3) will generally form asolution or suspension comprising the active agent to be delivered.Exemplary osmagents include high or low molecular weight compounds,organic and inorganic compounds such as salts, acids, bases, chelatingagents, sodium chloride, lithium chloride, magnesium chloride, magnesiumsulfate, lithium sulfate, potassium chloride, sodium sulfite, calciumbicarbonate, sodium sulfate, calcium sulfate, calcium lactate,d-mannitol, urea, tartaric acid, raffinose, sucrose, alpha-d-lactosemonohydrate, glucose, combinations thereof and other similar orequivalent materials known to those of ordinary skill in the art.Preferred osmagents include potassium chloride, sodium tartrate,glucose, mannitol, sodium acetate, sodium chloride, sodium sulfate,sodium citrate, potassium tartrate, sorbitol, sucrose and combinationsthereof.

The layer (3) comprising the active agent can also comprise anosmopolymer such as the ones previously described for the core (2),preferably poly(alkylene oxide) and, more preferably, poly(ethyleneoxide) with an average molecular weight between about 100,000 and8,000,000.

The delivery device of the invention advantageously requires loweramounts of osmagent, osmopolymer or osmotically effective agent todeliver an active substance than is required by related osmotic devicescontaining the same amount of active substance. Accordingly, the presentdelivery device contains a higher relative loading of active substancethan other comparable osmotic devices containing the same absoluteamount of active substance, and is generally smaller and lighter thansuch other devices. In preferred embodiments, the percentage of activesubstance present in the entire device ranges from about 0.1% to about99% with respect to the total weight of the device.

The delivery device of the invention can also comprise adsorbents,acidifying agents, alkalizing agents, antioxidants, buffering agents,colorants, flavorants, sweetening agents, antiadherents, binders,diluents, direct compression excipients, disintegrants, tablet glidants,tablet or capsule opaquants and/or tablet polishing agents.

As used herein, the term “alkalizing agent” is intended to mean acompound used to provide alkaline medium for product stability. Suchcompounds include, by way of example and without limitation, ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodiumbicarbonate, sodium hydroxide, triethanolamine, and trolamine and othersknown to those of ordinary skill in the art.

As used herein, the term “acidifying agent” is intended to mean acompound used to provide an acidic medium for product stability. Suchcompounds include, by way of example and without limitation, aceticacid, amino acid, citric acid, fumaric acid and other alpha hydroxyacids, such as hydrochloric acid, ascorbic acid, and nitric acid andothers known to those of ordinary skill in the art.

As used herein, the term “adsorbent” is intended to mean an agentcapable of holding other molecules onto its surface by physical orchemical (chemisorption) means. Such compounds include, by way ofexample and without limitation, powdered and activated charcoal andother such materials known to those of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent whoinhibits oxidation and is thus used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, ascorbic acid, ascorbic palmitate,Vitamin E, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorous acid, monothioglycerol, propyl gallate, sodiumascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetalbisulfite and other such materials known to those of ordinary skillin the art.

As used herein, the term “buffering agent” is intended to mean acompound used to resist a change in pH upon dilution or addition of acidor alkali. Such compounds include, by way of example and withoutlimitation, potassium metaphosphate, potassium phosphate, monobasicsodium acetate and sodium citrate anhydrous and dehydrate and other suchmaterials known to those of ordinary skill in the art.

As used herein, the term “sweetening agent” is intended to mean acompound used to impart sweetness to a preparation. Such compoundsinclude, by way of example and without limitation, aspartame, dextrose,glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose andother such materials known to those of ordinary skill in the art.

As used herein, the expression “antiadherents” is intended to meanagents that prevent the sticking of tablet formulation ingredients tothe punches and dies in a tableting machine during production. Suchcompounds include, by way of example and without limitation, magnesiumstearate, calcium stearate, talc, glyceryl behenate, poly(ethyleneglycol), hydrogenated vegetable oil, mineral oil, stearic acid,combinations thereof and other such materials known to those of ordinaryskill in the art.

As used herein, the term “binders” is intended to mean substances usedto cause adhesion of powder particles in tablet granulations. Suchcompounds include, by way of example and without limitation, acacia,alginic acid, tragacanth, carboxymethylcellulose sodium, poly(vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose,gelatin, liquid glucose, methylcellulose, povidone and pregelatinizedstarch, combinations thereof and other materials known to those ofordinary skill in the art.

When needed, other binders may also be included in the present osmoticdevice. Exemplary binders include starch, poly(ethylene glycol), guargum, polysaccharide, bentonites, sugars, invert sugars, poloxamers(PLURONIC™ F68, PLURONIC™ F127), collagen, albumin, celluloses innonaqueous solvents, combinations thereof and the like. Other bindersinclude, for example, poly(propylene glycol),polyoxyethylene-polypropylene copolymer, polyethylene ester,polyethylene sorbitan ester, poly(ethylene oxide), microcrystallinecellulose, poly(vinylpyrrolidone), combinations thereof and and othersuch materials known to those of ordinary skill in the art.

As used herein, the term “diluent” or “filler” is intended to mean inertsubstances used as fillers to create the desired bulk, flow properties,and compression characteristics in the preparation of tablets andcapsules. Such compounds include, by way of example and withoutlimitation, dibasic calcium phosphate, kaolin, sucrose, mannitol,microcrystalline cellulose, powdered cellulose, precipitated calciumcarbonate, sorbitol, starch, combinations thereof and other suchmaterials known to those of ordinary skill in the art.

As used herein, the term “tablet direct compression excipient” isintended to mean a compound used in direct compression tabletformulations. Such compounds include, by way of example and withoutlimitation, dibasic calcium phosphate (e.g. Ditab™), microcrystallinecellulose, direct compression lactose (e.g. Tablettose™, Lactose DT)combinations thereof and other such materials known to those of ordinaryskill in the art.

As used herein, the term “glidant” is intended to mean agents used intablet and capsule formulations to improve flow-properties during tabletcompression and to produce an anti caking effect. Such compoundsinclude, by way of example and without limitation, colloidal silica,calcium silicate, magnesium silicate, silicon hydrogel, cornstarch,talc, combinations thereof and other such materials known to those ofordinary skill in the art.

As used herein, the term “lubricant” is intended to mean substances usedin tablet formulations to reduce friction during tablet compression.Such compounds include, by way of example and without limitation,calcium stearate, magnesium stearate, mineral oil, stearic acid, zincstearate, combinations thereof and other such materials known to thoseof ordinary skill in the art.

As used herein, the term “tablet/capsule opaquant” is intended to mean acompound used to used in tablet coatings or capsules providing usefulopacity which can aid the stability to the light in case of sensitiveagents. It may be used alone or in combination with a colorant. Suchcompounds include, by way of example and without limitation, titaniumdioxide and other such materials known to those of ordinary skill in theart.

As used herein, the term “tablet polishing agent” is intended to mean acompound used to impart brightness to the surface of the coated tablets.Such compounds include, by way of example and without limitation,carnauba wax, white wax, combinations thereof and other such materialsknown to those of ordinary skill in the art.

As used herein, the term “tablet disintegrant” is intended to mean acompound used in solid dosage forms to promote the disruption of thesolid mass into smaller particles which are more readily dispersed ordissolved. Exemplary disintegrants include, by way of example andwithout limitation, starches such as corn starch, potato starch,pre-gelatinized and modified starches thereof, sweeteners, clays, suchas bentonite, microcrystalline cellulose (e.g. Avicel™),carboxymethylcellulose calcium, cellulose polyacrylin potassium (e.g.Amberlite™), alginates, sodium starch glycolate, gums such as agar,guar, locust bean, karaya, pectin, tragacanth, combinations thereof andother such materials known to those of ordinary skill in the art.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to pharmaceutical preparations. Such compounds include,by way of example and without limitation, FD&C Red No. 3, FD&C Red No.20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No.5, D&C Red No. 8, caramel, and iron oxide (black, red, yellow), otherF.D. & C. dyes and natural coloring agents such as grape skin extract,beet red powder, beta-carotene, annato, carmine, turmeric, paprika,combinations thereof and other such materials known to those of ordinaryskill in the art.

As used herein, the term “flavorant” is intended to mean a compound usedto impart a pleasant flavor and often odor to a pharmaceuticalpreparation. Exemplary flavoring agents or flavorants include syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may also include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaveoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Other useful flavors include vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavors, which have been found to be particularly useful,include commercially available orange, grape, cherry and bubble gumflavors and mixtures thereof. The amount of flavoring may depend on anumber of factors, including the desired organoleptic effect. Flavorswill be present in any amount as desired by the artisan of ordinaryskill in the art. Particularly preferred flavors are the grape andcherry flavors and citrus flavors such as orange.

The delivery device of the invention can also include oils such as fixedoils, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil;fatty acids such as oleic acid, stearic acid and isostearic acid; andfatty acid esters such as ethyl oleate, isopropyl myristate, fatty acidglycerides and acetylated fatty acid glycerides. The device can alsoinclude alcohol such as ethanol, isopropanol, hexadecyl alcohol,glycerol and propylene glycol; glycerol ketals such as2,2-dimethyl-1,3-dioxolane-4-methanol; ethers such as poly(ethyleneglycol) 450; petroleum hydrocarbons such as mineral oil andpetrolatum; water; mixtures thereof; or a pharmaceutically suitablesurfactant, suspending agent or emulsifying agent.

Soaps and synthetic detergents may be employed as surfactants and asvehicles for detergent compositions. Suitable soaps include fatty acidalkali metal, ammonium, and triethanolamine salts. Suitable detergentsinclude cationic detergents such as dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergentssuch as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether andmonoglyceride sulfates, and sulfosuccinates; non-ionic detergents suchas fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene)-block-poly(oxypropylene) copolymers; amphotericdetergents such as alkyl β-aminopropionates and 2-alkylimidazolinequaternary ammonium salts; and mixtures thereof.

Various other components, not otherwise listed above, can be added tothe present formulation to provide a device with a desired releaseprofile. Such components include, by way of example and withoutlimitation, glycerylmonostearate, nylon, cellulose acetate butyrate,d,l-poly (lactic acid), 1,6-hexanediamine, diethylenetriamine, starches,derivatized starches, acetylated monoglycerides, gelatin coacervates,poly(styrene-maleic acid) copolymer, glycowax, castor wax, stearylalcohol, glycerol palmitostearate, poly ethylene, poly(vinyl acetate),poly(vinyl chloride), 1,3-butylene-glycoldimethacrylate,ethyleneglycol-dimethacrylate and methacrylate hydrogels.

It should be understood that the compounds used in the art ofpharmaceutical formulation generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

Active agents preferably include physiologically or pharmacologicallyactive substances that produce a systemic or localized effect or effectson animals and human beings. Active agents also include pesticides,herbicides, insecticides, antioxidants, plant growth instigators,sterilization agents, catalysts, chemical reagents, food products,nutrients, cosmetics, vitamins, sterility inhibitors, fertilityinstigators, microorganisms, flavoring agents, sweeteners, cleansingagents and other such compounds for pharmaceutical, veterinary,horticultural, household, food, culinary, agricultural, cosmetic,industrial, cleaning, confectionery and flavoring applications. Theactive agent can be present in its neutral, ionic, salt, basic, acidic,natural, synthetic, diastereometric, isomeric, enantiomerically pure,racemic, hydrate, chelate, derivative, analog, or other common form.

The drug delivery device of the invention can be used to deliver two ormore different active agents. Particular combinations of active agentscan be provided by the present delivery device. Some combinations ofactive agents include: 1) a first drug from a first therapeutic classand a different second drug from the same therapeutic class; 2) a firstdrug from a first therapeutic class and a different second drug from adifferent therapeutic class; 3) a first drug having a first type ofbiological activity and a different second drug having about the samebiological activity; 4) a first drug having a first type of biologicalactivity and a different second drug having a different second type ofbiological activity. Exemplary combinations of active agents aredescribed herein. The active agents can be delivered to the same ordifferent environments of use. Accordingly, the active agent can beindependently selected at each occurrence from therapeutic compoundssuch as an antibiotic agent, antihistamine agent, decongestant,anti-inflammatory agent, antiparasitic agent, antiviral agent, localanesthetic, antifungal agent, amoebicidal agent, trichomonocidal agent,analgesic agent, anti-arthritic agent, anti-asthmatic agent,anticoagulant agent, anticonvulsant agent, antidepressant agent,antidiabetic agent, antineoplastic agent, anti-psychotic agent,neuroleptic agent, antihypertensive agent, hypnotic agent, sedativeagent, anxiolytic energizer agent, antiparkinson agent, muscle relaxantagent, antimalarial agent, hormonal agent, contraceptive agent,sympathomimetic agent, hypoglycemic agent, antilipemic agent, ophthalmicagent, electrolytic agent, diagnostic agent, prokinetic agent, gastricacid secretion inhibitor agent, anti-ulcerant agent, anti-flatulentagent, anti-incontinence agent, cardiovascular agent or a combinationthereof.

Representative antibacterial substances include, for example,penicillins: penicillin G and V, penicillinase-resistant penicillin(methicillin, nafcillin, oxacilin, cloxacilin and dicloxacillin), andaminopenicillins: ampicillin, amoxicillin, cyclacillin; carboxy andureidopenicillines such as carbenicillin, ticarcillin, azlocillin,mezlocillin and piperacilllin; cephalosporins such as thefirst-generation cephalosporins such as cephalotin, cephalexin,cefazolin, second generation cephalosporins such as cefoxitin, cefaclor,cefuroxime, and third generation cephalosporins such as cefotaxime,ceftriaxone, ceftazidime; beta-lactam antibiotics such as imipenem,aztreonam; sulfonamides such as sulfisoxazole, sulfamethoxazole,sulfadiazine, sulfasalazine and trimethropim-sulfamethoxazole;tetracyclines such as oxytetracycline, methacycline, chlorotetracyclineand doxycycline; chloramphenicol, erythromycin, lincomycin, clindamycin,vancomycin, bacitracin; aminoglycoside antiobiotics such asstreptomycin, gentamicin, tobramycin, amikacin, kanamycin and neomycin;and quinolones such as nalidixic acid, norfloxacin, ciprofloxacin,cinoxacin, ofloxacin, enoxacin, lomefloxacin, amifloxacin andpefloxacin.

Representative antiparasitic compounds include anthelmintics such asivermectin, mebendazole, albendazole, piperazine, praziquantel,thiabendazole, and dapsone. Representative anti-malarial compoundsinclude chloroquine and its congeners, diaminopyrimidines, mefloquine,primaquine and pyrimethamine. Miscellaneous antiparasitic agents include8-hydroxyquinolines, metronidazole, quinacrine and paromomycin.

Representative antiviral compounds include acyclovir, gancyclovir,zanamivir, oseltamivir, GS 4104,2,3-didehydro-2,4-dideoxy-4-guanidinyl-N-acetylneuraminic acid, GG167(4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid),pencyclovir, RWJ-270201,(+/−)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N′-ethyl-N′-isopropylcarbamyl)pyrrolidine-4-carboxylicacid (A-192558), foscarnet, 6-Acetamido-5-amino- and-5-guanidino-3,4-dehydro-N-(2-ethylbutyryl)-3-piperidinecarboxylicacids, idoxuridine, trifluridine and vidarabine; anti-retroviralcompounds such as zidovudine, didadosine, estavudine; others such asinterferon, amantadine and rivavirine; neuraminidase inhibitors.

Representative antineoplastics include nitrogen mustards such asmechlorethamine chlorambucil, cyclophosphamide; ethylenimines andmethylmelamines such as triethylenemelamine, thiotepa,hexamethyl-melamine; alkyl sulfonates such as busulfan; nitrosureas suchas carmustine (BCNU), lomustine; dacarbazine; folic acid analogs such asmethotrexate; pyrimidine analogs such as fluorouracil, arabinosidecytisine; purine analogs such as mercaptopurine, azathiprine; vincaalkaloids such as vincristine, vinblastine, taxol; etoposide;antibiotics such as actinomycin D, daunorubicin, doxorubicin, bleomycin,mitomycin; cisplatin; hydroxyurea; procarbazine; aminoglutethimide;cisplatin and tamoxifen.

Representative anti-inflammatory and analgesic drugs include cortisone,hydrocortisone, prednisone, prednisolone, betamethasone, dexamethasoneand fluorocortisone; cyclooxygenase II inhibitors such as rofecoxib,celecoxib, flosulide, NS-398, DUP-697, meloxicam,6-methoxy-2-naphthylacetic acid, nabumetone, etodolac, nimesulide,SC-5766, SC-58215, T-614; salicylates such as salicylic acid, aspirinand diflunisal; pyrazolon derivates such as phenylbutazone andoxyphenbutazone; aminopyridines such as dipyrone, para-aminophenolderivates such as acetaminophen and phenacetin, indomethacin andsulindac; fenamates such as mefenamic acid; tolmetin; propionic acidderivates such as ibuprofen, naproxen, fenoprofen, ketoprofen,flurbiprofen and indoprofen; piroxicam, and diclofenac. Representativeopioid analgesics include morphine, codeine, meperidine and nalorphine.

Representative anti-incontinence agents include oxybutynin, tolterodine,and darifenacin.

Representative gastric acid secretion inhibitors include ranitidine andomeprazole, which are known as H2 blocker or acid-suppressing drugs.

Representative drugs used in the treatment of gout include colchicine,allopurinol, probenecid and sulphinpirazone.

Representative antihistamines and decongestants include the firstgeneration compounds such as diphenhydramine, pirilamine,chlorpheniramine, brompheniramine, promethazine; H1 antagonists such asacrivastine, astemizole, azelastine, cetirizine, ebastine, epinastine,fexofenadine, loratadine, mizolastine, norastemizol, prometazine andterfenadine.

Representative sympathomimetic drugs include epinephrine, amphetamine,ephedrine and norepinephrine.

Representative antiasthmatic drugs include methylxanthines such astheophylline; from corticoids such as beclomethasone dipropionate,budesonide, flunisolide, prednisone; bronchodilators such as albuterol,salbutamol, salmetherol, terbutaline; antimuscharinic agents such asipratopium bromide; and cromolyn sodium.

Representative local anesthetics include benzocaine, procaine,lidocaine, cocaine, tetracaine, bupivacaine and dibucaine.

Representative muscle relaxants and antispasmodic agents includealcuronium, alosetron, aminophylline, baclofen, carisoprodol,chlorphenesin, chlorphenesin carbamate, chlorzoxazone, chlormezanone,cyclobenzaprine, dantrolene, decamethonium, diazepam, dyphylline,eperisione, ethaverine, gallamine triethiodide, hexafluorenium,mephenesin, metaxalone, methocarbamol, metocurine iodide, orphenadrine,pancuronium, papaverine, pipecuronium, pridinol, succinylcholine,theophylline, tizanidine, tolperisone, tubocurarine, vecuronium,idrocilamide, ligustilide, cnidilide, senkyunolide, baclofen,trihexylphenidyl, pridinol, and biperiden.

Representative antiparkinson disease compounds include levodopa,carbidopa, benceracide, amantadine, bromocriptine and pergolide.

Representative antidepressant compounds include tricyclic agents such asamitriptyline, imipramine, clomipramine, doxepine; monoamine oxidaseinhibitors such as isocoboxazid, phenelzine and tranylcypromine;fluoxetine, fluvoxamine, paroxetine, sertraline, alprazolam,venlafaxine, bupropione and trazodone.

Representative anticonvulsants include hydantoins such as phenytoin,barbiturates and deoxy derivates such as phenobarbital and primidone;carbamazepine, ethosuximide, valproic acid; and benzodiacepines such asdiazepam and clonazepam.

Representative antipsychotics include risperidone, olanzapine,clozapine, sertindole, ziprasidone, quetiapine, sulpiride, pimozide,clothiapine, molindone, loxapine, trifluoperazine, haloperidol,flupenthixol, chlorpromazine, chlorprothixene, clopenthixol, droperidol,perphenazine, fluphenazine, lithium, mesoridazine, spiperone, promazine,prochlorperazine, thioridazine, thiothixene, triflupromazine andraclopride, and trifluoperazine.

Representative hypnotics and sedatives include barbiturates such aspentobarbital sodium, phenobarbital, secobarbital, thiopental;benzodiazepines such as diazepam, alprazolam, chlordiazepoxide,clonazepam, lorazepam, oxazepam; buspirone, meprobamate, zolpidem andzoplicone.

Representative hypoglucemic agents include insulin, insulin zinc,isophane insulin, protamine zinc insuline and extended insulin zincsuspension; sulfonylureas such as tolbutamide, chlorpropamide,acetohexamide, glyburide, glipizide, glicazide; biguanides such asphenformin, metformin; ciglitazone, troglitazone, and acarbose.

Representative antidiuretics drugs include inhibitors of carbonicanhydrase such as acetazolamide, chortalidone, indapamine;benzothiadiazides such as chlorothiazide, hydrochlorothiazide;ethacrynic acid, furosemide, bumetanide; aldosterone antagonists such asspironolactone; triamtirene and amiloride.

Representative antihypertensive and cardiovascular drugs includeinhibitors of the renin-angiotensin system such as enalapril,lisinopril, ramipril, captopril, perindopril, trandolapril; angiotensinII receptors antagonists such as losartan; calcium channel blockers:nifedipine, amlodipine, nitrendipine, nimodipine, diltiazem, verapamil;simpathocolitic agents; adrenergic antagonists; atenolol, propanolol,nadolol, sotalol, timolol, metropolol, acebutolol, carvedilol;adrenergic agonists; prazosin, fentolamine; centrally acting agents suchas methyldopa, clonidine, guanfacine, reserpine; direct arterial andvenous vasodilators such as sodium nitroprusside, nitroglicerin,isosorbide 5-mononitrate, isosorbide dinitrate; antiarrhythmic agentssuch as quinidine, procainamide, phenytoin, lidocaine, mexiletine,propafenone, flecainide, encainide, propranolol, acebutolol, amiodarone,sotalol, verapamil and diltiazem; digitalis; and cardiac glycosides suchas digoxine, digitoxine, amrinone, and milrinone.

Representative anticoagulants include heparin, warfarin, dicoumarol;thrombolytic agents such as streptokinase, tissue plasminogen activator(t-PA) urokinase and antiplatelet drugs such as dipyridamole,ticlopidine, and sulfinpyrazone.

Representative prokinetic gastrointestinal drugs include cisapride,clevopride, domperidone, metoclopramide and mosapride.

Representative anti-spasmodic and muscle contractants include atropine,scopolamine, methoescopolamine and oxyphenonium.

Representative steroidal drugs include prednisolone, cortisone, cortisoland triamcinolone; androgenic steroids such as methyltesterone, andfluoxmesterone; estrogenic steroids such as 17β-estradiol, α-estradiol,estriol, α-estradiol 3 benzoate, and 17-ethynylestradiol-3-methyl ether;and progestational steroids such as progesterone,19-nor-pregn-4-ene-3,20-dione,17-hydroxy-19-nor-17-α-pregn-5(10)-ene-20-yn-3-one,17α-ethynyl-17-hydroxy-5(10)-estren-3-one, and 9β,10α-pregna-4,6-diene-3,20-dione.

Representative ophthalmic agents include pilocarpine, pilocarpine saltssuch as pilocarpine nitrate, pilocarpine hydrochloride, dichlophenamide,atropine, atropine sulfate, scopolamine and eserine salicylate.

Representative nutritional agents include ascorbic acid, niacin,nicotinamide, folic acid, choline biotin, panthothenic acid, and vitaminB12, essential amino acids, and essential fats.

Representative electrolytes include calcium gluconate, calcium lactate,potassium chloride, potassium sulfate, sodium chloride, sodium fluoride,ferrous lactate, ferrous gluconate, ferrous sulfate, ferrous fumarateand sodium lactate.

The above-mentioned list should not be considered exhaustive and ismerely exemplary of the many embodiments considered within the scope ofthe invention. Many other active compounds can be administered with thedevice of the present invention.

The therapeutic compound(s) contained within the present device can beformulated as its pharmaceutically acceptable salts. As used herein,“pharmaceutically acceptable salts” refers to derivatives of thedisclosed compounds wherein the therapeutic compound is modified byreacting it with an acid or base as needed to form an ionically boundpair. Examples of pharmaceutically acceptable salts include conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Suitablenon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric,nitric and others known to those of ordinary skill in the art. The saltsprepared from organic acids such as amino acids, acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, and others knownto those of ordinary skill in the art. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parenttherapeutic compound which contains a basic or acidic moiety byconventional chemical methods. Lists of other suitable salts are foundin Remington's Pharmaceutical Sciences, 17^(th). ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the relevant disclosure of which ishereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith tissues of human beings and animals and without excessive toxicity,irritation, allergic response, or any other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used in this disclosure, the term vitamin refers to trace organicsubstances that are required in the diet. For the purposes of thepresent invention, the term vitamin(s) include, without limitation,thiamin, riboflavin, nicotinic acid, pantothenic acid, pyridoxine,biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A,vitamin D, vitamin E and vitamin K. Also included within the termvitamin are the coenzymes thereof. Coenzymes are specific chemical formsof vitamins and can include thiamin pyrophosphates (TPP), flavinmononucleotide (FMN), and flavin adenine dinucleotive (FAD).Nicotinamide adenine dinucleotide (NAD), Nicotinamide adeninedinucleotide phosphate (NADP), Coenzyme A (CoA), pyridoxal phosphate,biocytin, tetrahydrofolic acid, coenzyme B12, lipolysine,11-cis-retinal, and 1,25-dihydroxycholecalciferol. The term vitamin(s)also includes choline, carnitine, and alpha, beta, and gamma carotene.

As used in this disclosure, the term “mineral” refers to inorganicsubstances, metals, and the like required in the human diet. Thus, theterm “mineral” as used herein includes, without limitation, calcium,iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromium,mixtures thereof and others known to those of ordinary skill in the art.

The term “dietary supplement” as used herein means a substance, whichhas an appreciable nutritional effect when, administered in smallamounts. Dietary supplements include, without limitation, suchingredients as bee pollen, bran, wheat germ, kelp, cod liver oil,ginseng, and fish oils, amino-acids, proteins, plant extracts, plantpowder, herbs, herbal extracts and powders, vitamins, minerals,combinations thereof and others known to those of ordinary skill in theart. As will be appreciated, essentially any dietary supplement may beincorporated into the present osmotic device.

The amount of therapeutic compound incorporated in each device of theinvention will be at least one or more dosage form and can be selectedaccording to known principles of pharmacy. An effective amount oftherapeutic compound is specifically contemplated. By the term“effective amount”, it is understood that, with respect to, for example,pharmaceuticals, a pharmaceutically effective amount is contemplated. Apharmaceutically effective amount is the amount or quantity of a drug orpharmaceutically active substance which is enough for the required ordesired therapeutic response, or in other words, the amount, which issufficient to elicit an appreciable biological response when,administered to a patient. The appreciable biological response may occuras a result of administration of single or multiple unit doses of anactive substance. Depending upon the active substance used and upon theamount of active substance present in a particular device according tothe invention, a unit dose may comprise one or more such devices. Asused with reference to a vitamin or mineral, the term “effective amount”means an amount at least about 10% of the United States RecommendedDaily Allowance (“RDA”) of that particular ingredient for a patient. Forexample, if an intended ingredient were vitamin C, then an effectiveamount of vitamin C would include an amount of vitamin C sufficient toprovide 10% or more of the RDA. Typically, where the tablet includes amineral or vitamin, it will incorporate higher amounts, preferably about100% or more of the applicable RDA.

When combinations of active agents are used, one or both of the activeagents can be present in a sub-therapeutic amount. As used herein, asub-therapeutic amount is that amount of first drug which provides lessthan a normal therapeutic response in patient to which the first drug isadministered in the absence of the second drug of the combination. Inother words, the first and second drugs may together provide anenhanced, improved, additive or synergistic therapeutic benefit ascompared to the administration of each drug alone, i.e., in the absenceof the other drug.

For nasal administration of therapeutic compounds, the device of theinvention may be included in a paste, cream or ointment containing theappropriate solvents (such as water, aqueous, nonaqueous, polar, apolar,hydrophobic, hydrophilic and/or combinations thereof) and optionallyother compounds (stabilizers, perfumes, antimicrobial agents,antioxidants, pH modifiers, surfactants and/or bioavailabilitymodifiers). Bioavailability enhancers such as alcohols or othercompounds that enhance the penetration of the therapeutic compound fromthe pharmaceutical formulation into the nasal mucosa may be needed toprepare suitable formulations for nasal administration.

For oral, buccal, and sublingual administration, the delivery device maybe in the form of a caplet or tablet. For rectal administration, theosmotic device can be included in a suppository or tablet for release ofa therapeutic compound into the intestines, sigmoid flexure and/orrectum. For cutaneous, subcutaneous, otic, intraperitoneal, ophthalmicand implant applications, the device is a solid dosage form adapted forsuch application and is preferably a tablet.

The device of the invention can be prepared according to the methodsdisclosed herein or those well known in the art. For example, accordingto a preferred process, the hydrophilic polymer or a mixture thereof ismixed with suitable excipients in solid form, is then moistened andsieved through a screen and dried for several hours in a convectionoven. The dried granulate is then screened and mixed with other suitableexcipients and the homogeneous mixture is subsequently compressed toform 4 to 10 mm diameter expandable placebo cores. A mixture comprisingan active agent and a suitable excipient is then compressed over thecore (2) to form 6 to 12 mm diameter uncoated tablets. Uncoated tabletsare then covered preferably with a mixture of selected polymers thatconstitute the wall (4). Subsequently, the wall (4) is perforated at anylocation with a laser, drill or other mechanical means known to those ofordinary skill in the art. Optionally, the tablets may be further coatedwith an external film comprising an active agent for immediate orsustained delivery to the environment of use.

If desired, the device of the invention can be coated with a finishcoating as is commonly done in the art to provide the desired shine,color, taste or other aesthetic characteristics. Materials suitable forpreparing the finish coating are well known to those of ordinary skillin the art.

The following examples should not be considered exhaustive, but merelyillustrative of only a few of the many embodiments included within thescope of the present invention. The methods described herein can befollowed to prepare delivery devices according to the invention.

EXAMPLE 1

Biconvex-shaped expandable cores about 7.0 mm in diameter were preparedwithout active agent as follows. 20.85 g of lactose monohydrate, 18.25 gof hydroxypropyl methylcellulose (HPMC; 2208 type; Dow Chemical U.S.A.);1.8 g of poly(ethylene oxide) (4,000,000 molecular weight), 2.15 g ofpoly(vinylpyrrolidone), 0.30 g of red ferric oxide, and 0.45 g ofsilicon dioxide were mixed then sieved through a 40-mesh screen. Alcohol(96°, 30 ml) was slowly added to the dry blend until a wet blend wasachieved. The wet blend was then sieved through a 10-mesh screen and thegranular mass obtained was dried for several hours at 45° C. in aconvection oven. The dried granulate was then sieved through a 20-meshscreen. The sieved granulate was mixed with 0.75 g of magnesium stearateand 0.45 g of silicon dioxide (both having been previously sievedthrough a 60-mesh screen) and then mixed in a V-blender for 5 minutes.The homogeneous mixture was subsequently compressed to form biconvexcores, which individually weighed 90.0 mg.

A first layer comprising the active agent was prepared as follows 20.75g of cisapride monohydrate, 28.15 g of microcrystalline cellulose, 37.50g. of sodium chloride, 45.00 g of poly(ethylene oxide) (200,000molecular weight), 0.37 g of colloidal silicon dioxide and 15.75 g ofpoly(vinylpyrrolidone) were mixed and then sieved through a 40-meshscreen. The sieved mixture was then granulated with alcohol (96°, 40 mlhaving 0.85 g of polysorbate 20 previously dissolved in it). All theingredients were mixed for a few additional minutes. The granular masswas then dried for several hours at 45° C. in a convection oven. Driedgranulate was then sieved through a 20 mesh screen. The sieved mixturewas mixed with 1.25 g of magnesium stearate and 0.38 g of colloidalsilicon dioxide (both previously sieved through a 60 mesh screen) in aV-blender for 5 minutes to form a homogeneous drug-containingcomposition. The drug-containing composition was compressed about thepreviously formed expandable cores to form biconvex uncoated cores,about 9.25 mm in diameter, each weighing about 390 mg.

A wall for covering the uncoated cores was prepared as follows. Apolymeric suspension was prepared by dissolving 27.36 g of celluloseacetate (average molecular weight 40,000, acetyl content 32% by weightCA), 6.84 g of ammonium methacrylate copolymer (Eudragit™ RS 100, RöhmPharma) and, 5 weight percent poly(ethylene glycol), in a mixture ofmethylene chloride-methyl alcohol 80:20 v/v. The polymeric suspensionwas then sprayed onto the uncoated tablets to form coated tablets havinga wall weighing about 31.63 mg. Two 0.75-mm holes were drilled throughthe coating in both faces of the device to form a delivery deviceaccording to the invention.

FIG. 2 discloses the results of a drug delivery assay performed on thedelivery device in a USP type 3 Apparatus, in distilled water (250 ml,30 DPM at 37° C.). The release data are summarized in the table below.

Accumulative Amount Hours Released (%) 1  2.4 3 27.8 6 64.8 9 85.6 1291.7 15 93.3 21 94.0 24 94.7

EXAMPLE 2

Biconvex-shaped cores of 8.0 mm in diameter were prepared without activeagent as follows. 21.50 g of hydroxypropyl methylcellulose (HPMC; 2208type), 23.75 g of poly(ethylene oxide) (300,000 molecular weight), 2.71g of poly(vinylpyrrolidone), 0.35 g of red ferric oxide, and 0.53 g ofsilicon dioxide were mixed and sieved through a 40-mesh screen. Then,alcohol (96°; 40 ml) was slowly added to the dry blend to form a wetblend which was sieved through a 10-mesh screen. The resulting granularmass was dried for several hours at 45° C. in a conventional oven, andthen sieved through a 20-mesh screen. The granulate was mixed with 0.88g of magnesium stearate and 0.53 g of silicon dioxide (both after havingbeen sieved through a 60 mesh screen) in a V-blender for 5 minutes. Thehomogeneous mixture was subsequently compressed to form biconvex cores,which weighed about 100. mg each.

A first layer comprising the active agent was prepared as follows. 16.50g of micronized nifedipine, 15.00 g of microcrystalline cellulose, 32.05g of sodium chloride, 37.50 g of poly(ethylene oxide) (200,000 molecularweight), 0.75 g of colloidal silicon dioxide and 19.25 g ofpoly(vinylpyrrolidone) were mixed and sieved through a 40 mesh screen.The sieved mixture was granulated with alcohol (96°; 35 having 0.70 g ofpolysorbate 20 previously dissolved in it). All the ingredients weremixed for a few additional minutes. The granular mass was dried forseveral hours at 45° C. in a convection oven, and the dried granulatewas sieved through a 20-mesh screen. The sieved blend was then mixedwith 1.75 g of magnesium stearate and 0.75 g of colloidal silicondioxide (both having been previously sieved through a 60-mesh screen) ina V-blender for 5 minutes. The homogeneous mixture was subsequentlycompressed about the expandable cores to form biconvex dosage units ofabout 10 mm in diameter to form the coated device core. The averageweight of the cores was about 360 mg.

A wall surrounding the uncoated core was prepared as follows. A polymersuspension was prepared by dissolving 13.3 mg of cellulose acetate(average molecular weight 40,000, acetyl content 32% by weight CA), 13.3mg of cellulose acetate (average molecular weight 38,000, acetyl content39.8% by weight CA), 6.65 g of ammonium methacrylate copolymer(Eudragit™ RS 100, Röhm Pharma) and 1.75 g of poly(ethylene glycol), ina mixture of methylene chloride-methyl alcohol 80:20 v/v (493/123 ml).The polymeric mixture was sprayed onto the dosage units to form coatedtablets each having a wall weighing about 35 mg. Two 0.75-mm holes werethen drilled through the wall, one on each face of the device.

FIG. 3 depicts the release profile for the tablets of this example. Therelease profile was determined in a USP type 3 Apparatus, in distilledwater (250 ml., 30 DPM at 37° C.). The actual release data obtained aresummarized below.

Accumulative Amount Hours Released (%) 1  0.4 3 13.4 6 42.6 9 63.6 1277.7 15 87.9 21 94.5 24 94.8

EXAMPLE 3

Biconvex-shaped expandable cores about 7 mm in diameter were prepared asfollows. 20.85 g of lactose monohydrate, 18.25 g of hydroxypropylmethylcellulose (HPMC, 2208 type), 1.8 g of poly(ethylene oxide)(4,000,000 molecular weight), 2.15 g of poly(vinylpyrrolidone), 0.30 gof red ferric oxide as coloring agent and 0.45 g of silicon dioxide weremixed, and the mix was sieved through a 40-mesh screen. Then, alcohol(96°; 30 ml) was slowly added to the dry blend until a wet blend wasachieved. The wet blend was then sieved through a 10 mesh screen and theresulting granulate was dried in a convection oven for several hours.The dried granulate was sieved through a 20-mesh screen and mixed with0.75 g magnesium stearate and 0.45 g silicon dioxide (both having beenpreviously sieved through a 60-mesh screen) in a V-blender for 5minutes. The homogeneous mixture was subsequently compressed to formbiconvex cores each weighing about 90 mg.

A first layer containing the active agent was prepared as follows. 42.43g of venlafaxine hydrochloride, 25.22 g of microcrystalline cellulose,37.5 g of sodium chloride, 45 g of poly(ethylene oxide) (200,000molecular weight), 0.35 g of colloidal silicon dioxide and 12.00 g ofpoly(vinylpyrrolidone) were mixed. The blend was sieved through a40-mesh screen. This mixture was granulated with alcohol (96°; 40 ml,having 0.85 g of polysorbate 20 previously dissolved in it). All theingredients were mixed for a few additional minutes. The granular masswas dried for several hours at 45° C. in a convection oven. Then the drygranulate was sieved through a 20-mesh screen. The sieved blend wasmixed with 1.25 g of magnesium stearate and 0.40 g of colloidal silicondioxide (having both been previously sieved through a 60 mesh screen) ina V-blender for 5 minutes. The homogeneous mixture was subsequentlycompressed about the expandable cores to form biconvex-shaped uncoatedcores about 9.25 mm in diameter, each weighing about 330 mg.

A wall for covering the uncoated cores was prepared as follows. Apolymer suspension was prepared by dissolving 27.36 g of celluloseacetate (average molecular weight 40,000, acetyl content 32% by weightCA), 6.84 g of ammonium methacrylate copolymer (Eudragit™ RS 100, RöhmPharma) and 1.84 g of poly(ethylene glycol), in a methylenechloride-methyl alcohol mixture of about 80:20 v/v (493 ml/123 ml). Thispolymer mixture was sprayed onto the uncoated cores to form coatedcores, each having a wall weighing about 32.3 mg. Two 0.75-mm holes weredrilled through the coating on both faces of the device.

FIG. 4 depicts the release profile obtained with the device of thisexample. The release profile was determined in a USP Type 2 Apparatus,in distilled water, 800 ml, 100 rpm at 37° C. The actual release dataobtained are summarized below.

Accumulated Amount Hours Dissolved (%) 1  4.7 3 19.1 6 48.5 9 66.9 1273.3 15 75.5 21 78.5 24 80.9

EXAMPLE 4 Device Having a Rapid Release External Coating Containing Drug

A drug dosage form adapted, designed and shaped as an osmotic deliverysystem, containing two layers surrounding a central core, includingactive agent and hydrophilic polymer in the first layer and, celluloseacetate and ammonium methacrylate copolymer in the second layer, andhaving a rapid release external coating was manufactured as follows.

Round, biconvex-shaped cores of 7.0 mm in diameter were prepared withoutactive agent as follows: 20.85 g of lactose monohydrate as fillingmaterial; 18.25 g of hydroxypropyl methylcellulose (HPMC of 2208 type)as hydrophilic polymer; 1.8 g of polyethylene oxide having a 4,000,000molecular weight; 2.15 g of poly(vinylpyrrolidone); 0.30 g of red ferricoxide as coloring agent and 0.45 g of silicon dioxide were mixed and themix was passed through a 40-mesh screen. Then, alcohol 96° was slowlyadded to the dry blend until a wet blend was achieved. The wet blend waspassed through a 10-mesh screen and the granular mass was dried forseveral hours at 45° C. in a convection oven. Then the dry granulate waspassed through a 20-mesh screen. The screened granulation was mixed with0.75 g of magnesium stearate and 0.45 g of silicon dioxide (bothpreviously passed through a 60-mesh screen) and placed into a V-blenderfor 5 minutes. The homogeneous mixture was subsequently compressed toform biconvex cores which individually weighed 90.0 mg.

The first layer was prepared containing the active agent as follows:20.75 g of Cisapride monohydrate; 28.15 g of microcrystalline cellulose;37.50 g of sodium chloride; 45.00 g of polyethylene oxide having a200,000 molecular weight; 0.37 g of colloidal silicon dioxide and 15.75g of poly vinylpyrrolidone were mixed and the mix was passed through a40-mesh screen. This mixture was granulated with alcohol 96° togetherwith 0.85 g of polysorbate 20 previously dissolved in it and all theingredients were mixed for a few additional minutes. The granular masswas dried for several hours at 45° C. in a convection oven. Then the drygranulate was passed through a 20-mesh screen.

The screened blend was mixed with 1.25 g of magnesium stearate and 0.38g of colloidal silicon dioxide (both previously passed through a 60-meshscreen) and placed into a V-blender for 5 minutes. The homogeneousmixture was subsequently compressed surrounding the central core whichwas obtained in the first part, obtaining 9.25-mm diameter biconvextablets. The average weight of the cores was 390.0 mg.

The second layer was formed by the above tablets which were then coatedwith a semipermeable wall. A polymer suspension was prepared dissolving76 weight percent of cellulose acetate; 19 weight percent of ammoniummethacrylate copolymer (Eudragit RS 100, Röhn Pharma) and, 5 weightpercent polyethylene glycol 400, with the total weight percent equal to100, in a mixture of methylene chloride-methyl alcohol 80:20 v/v(volume/volume). This polymer mixture was sprayed onto the tablets in aconventional pan coater to obtain film-coated tablets whose membranecoating weighed 31.63 mg. A 0.75-mm hole was drilled through the coatingin both faces of the device.

A rapid release external coating was prepared by mixing 33.48 g ofranitidine HCl, 131.02 g of microcrystalline cellulose, 25.00 g ofpovidone, 8.00 g of polyethylene glycol 6000, 1.70 g of polyethyleneglycol 400 and 1.00 g of colloidal silicon dioxide. The mixture wasblended to homogenize; then, 2.00 g of magnesium stearate was added aslubricant. This blend was tabletted to 800 mg-1000 mg/core and hardnessof 8-12 kP with flat faced, 13.0-mm diameter punches. The slugs weremilled by passing through a standard USP 20-mesh screen and were blendedwith 122.30 g of microcrystalline cellulose, 0.50 g of colloidal silicondioxide, 5.00 g of croscarmellose sodium and 2.00 g of magnesiumstearate. This final blend was compressed over the film-coated tabletsby compression using biconcaves, 13.0-mm diameter punches. Coatingweight: 332 mg. Hardness from 10 to 15 kp.

The final coating was prepared by mixing 10,89 g of hydroxypropylmethylcellulose 2910, 3.10 g of polyethylene glycol 6000, 3.99 g oftitanum dioxide, 22.00 mg of Aluminum Lake Red Ponceau in a mixture of280 ml of methylene chloride and 120 ml of alcohol 96°. This polymermixture was sprayed onto the tablets in a conventional pan coater toobtain film-coated tablets whose membrane coating weighed 18 mgapproximately.

EXAMPLE 5 Device Having a Controlled, Slow or Delayed Release ExternalCoating Containing Drug

A drug dosage form adapted, designed and shaped as an osmotic deliverysystem, containing two layers surrounding a central core, includingactive agent and hydrophilic polymer in the first layer and, celluloseacetate and ammonium methacrylate copolymer in the second layer, andhaving a delayed release external coating was manufactured as follows:

Round, biconvex-shaped cores of 7.0 mm in diameter were prepared withoutactive agent as follows: 20.85 g of lactose monohydrate as fillingmaterial; 18.25 g of hydroxypropyl methylcellulose (HPMC of 2208 type)as hydrophilic polymer; 1.8 g of polyethylene oxide having a 4,000,000molecular weight; 2.15 g of poly(vinylpyrrolidone); 0.30 g of red ferricoxide as coloring agent and 0.45 g of silicon dioxide were mixed and themix was passed through a 40-mesh screen. Then, alcohol 96° was slowlyadded to the dry blend until a wet blend was achieved. The wet blend waspassed through a 10-mesh screen and the granular mass was dried forseveral hours at 45° C. in a convection oven. Then the dry granulate waspassed through a 20-mesh screen. The screened granulation was mixed with0.75 g of magnesium stearate and 0.45 g of silicon dioxide (bothpreviously passed through a 60-mesh screen) and placed into a V-blenderfor 5 minutes. The homogeneous mixture was subsequently compressed toform biconvex cores that individually weighed 90.0 mg.

The first layer was prepared containing the active agent as follows:20.75 g of cisapride monohydrate; 28.15 g of microcrystalline cellulose;37.50 g of sodium chloride; 45.00 g of polyethylene oxide having a200,000 molecular weight; 0.37 g of colloidal silicon dioxide and 15.75g of poly(vinylpyrrolidone) were mixed and the mixture was passedthrough a 40-mesh screen. This mixture was granulated with alcohol 96°together with 0.85 g of polysorbate 20 previously dissolved in it andall the ingredients were mixed for a few additional minutes. Thegranular mass was dried for several hours at 45° C. in a convectionoven. Then the dry granulate was passed through a 20-mesh screen. Thescreened blend was mixed with 1.25 g of magnesium stearate and 0.38 g ofcolloidal silicon dioxide (both previously passed through a 60-meshscreen) and placed into a V-blender for 5 minutes. The homogeneousmixture was subsequently compressed about the central core which wereobtained in the first part, to form 9.25-mm diameter biconvex tablets.The average weight of the cores was 390.0 mg.

The second layer was formed by the above tablets which were then coatedwith a semipermeable wall. A polymer suspension was prepared dissolving76 weight percent of cellulose acetate; 19 weight percent of ammoniummethacrylate copolymer (Eudragit RS 100, Röhn Pharma) and, 5 weightpercent polyethylene glycol 400, with the total weight percent equal to100, in a mixture of methylene chloride-methyl alcohol 80:20 v/v(volume/volume). This polymer mixture was sprayed onto the tablets in aconventional pan coater to obtain film-coated tablets whose membranecoating weighed 31.63 mg. A 0.75-mm hole was drilled through the coatingin both faces of the device.

A delayed release external coating was prepared by mixing 33.48 g ofranitidine HCl, 131.02 g of microcrystalline cellulose, 25.00 g ofpovidone, 8.00 g of polyethylene glycol 6000, 1.70 g of polyethyleneglycol 400 and 1.00 g of colloidal silicon dioxide. The mixture wasblended to homogenize; then, 2.00 g of magnesium stearate was added aslubricant. This blend was tabletted to form 800 mg-1000 mg cores havinga hardness of 8-12 kP with flat faced, 13.0-mm diameter punches. Theslugs were milled by passing through a standard USP 20-mesh screen andwere blended with 122.30 g of microcrystalline cellulose, 0.50 g ofcolloidal silicon dioxide, 5.00 g of croscarmellose sodium and 2.00 g ofmagnesium stearate. This final blend was compressed over the film-coatedtablets by compression using biconcaves, 13.0-mm diameter punches.Coating weight: 332 mg. Hardness from 10 to 15 kp.

The final coating was prepared by mixing 21.80 g of methacrylic acidcopolymer, USP Type A, 1.45 g of polyethylene glycol 6000, 4.60 g oftitanum dioxide, 7.00 g of talc and 0.15 mg of Red Ferric Oxide in 780ml of isopropyl alcohol. This polymer mixture was sprayed onto thetablets in a conventional pan coater to obtain film-coated tablets whichmembrane coating weighed 35 mg approximately.

The above is a detailed description of particular embodiments of theinvention. It is recognized that departures from the disclosedembodiments may be made within the scope of the invention and thatobvious modifications will occur to a person skilled in the art. Thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentswhich are disclosed herein and still obtain a like or similar resultwithout departing from the spirit and scope of the invention. All of theembodiments disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure.

I claim:
 1. A device for the controlled delivery of at least one activeagent to an environment of use, wherein the device comprises: a coreexpandable in a fluid from the environment of use, the core beingapproximately centrally located in the device; a layer comprising atleast one first active agent, wherein the layer is in contact with andsurrounds the core; and a membrane in contact with and surrounding thelayer and comprising at least one preformed passageway for delivery ofthe at least one active agent by osmotic pumping and plural microporesfor delivery of the at least one active agent by diffusion, and themembrane further comprising one or more cellulose esters, one or morepoly(methacrylate) copolymer salts and one or more plasticizers, whereinthe membrane permits delivery of the at least one active substancethrough a combination of diffusion and osmotic pumping.
 2. A deviceaccording to claim 1 further comprising a drug-containing coat externalto the membrane and comprising a second active agent, wherein thedrug-containing coat provides an immediate, rapid, controlled or delayedrelease of the second active agent and the external coat surrounds atleast a portion of the membrane.
 3. A device according to claim 2,wherein the first and second active agents are different and areindependently selected at each occurrence from the group consisting ofan antibiotic agent, antihistamine agent, decongestant,anti-inflammatory agent, antiparasitic agent, antiviral agent, localanesthetic, antifungal agent, amoebicidal agent, trichomonocidal agent,analgesic agent, anti-arthritic agent, anti-asthmatic agent,anticoagulant agent, anticonvulsant agent, antidepressant agent,antidiabetic agent, antineoplastic agent, anti-psychotic agent,neuroleptic agent, antihypertensive agent, hypnotic agent, sedativeagent, anxiolytic energizer agent, antiparkinson agent, muscle relaxantagent, antimalarial agent, hormonal agent, contraceptive agent,sympathomimetic agent, hypoglycemic agent, antilipemic agent, ophthalmicagent, electrolytic agent, diagnostic agent, prokinetic agent, gastricacid secretion inhibitor agent, anti-ulcerant agent, anti-flatulentagent, anti-incontinence agent, and cardiovascular agent.
 4. A deviceaccording to claim 3, wherein the first active agent is a prokineticagent and the second active agent is a gastric acid secretion inhibitoragent.
 5. A device according to claim 3, wherein the first active agentis a decongestant and the second active agent is an antihistamine.
 6. Adevice according to claim 3, wherein the first active agent is a firstanti-incontinence agent and the second active agent is a differentsecond anti-incontinence agent.
 7. A device according to claim 6,wherein the anti-incontinence agents are selected from the groupconsisting of oxybutynin, tolterodine and darifenacin.
 8. A deviceaccording to claim 3, wherein the first active agent is a firstantihypertensive agent and the second active agent is a different secondantihypertensive agent.
 9. A device according to claim 8, wherein theantihypertensive agents are selected from the group consisting of acalcium channel blocker agent, an angiotensin converting enzymeinhibitor agent, a diuretic agent and a beta-adrenergic antagonistagent.
 10. A device according to claim 3, wherein the first active agentis an antidepressant agent and the second active agent is ananti-psychotic agent.
 11. A device according to claim 3, wherein thefirst active agent is a first analgesic or anti-inflammatory agent, andthe second active agent is a different second analgesic oranti-inflammatory agent.
 12. A device according to claim 11, wherein theanalgesic and anti-inflammatory agents are selected from the groupconsisting of an non-steroidal anti-inflammatory agent, a steroidalanti-inflammatory agent, an opioid receptor agonist agent, and aselective or specific COX-II inhibitor agent.
 13. A device according toclaim 3, wherein the first active agent is an antiviral agent and thesecond active agent is an antihistamine agent.
 14. A device according toclaim 3, wherein the first active agent is a muscle relaxant agent andthe second active agent is an anti-inflammatory or analgesic agent. 15.A device according to claim 14, wherein the first active agent ispridinol and the second active agent is a selective or specific COX-IIinhibitor agent.
 16. A device according to claim 2, wherein the firstand second active agents are the same and are selected from the groupconsisting of an antibiotic agent, antihistamine agent, decongestant,anti-inflammatory agent, antiparasitic agent, antiviral agent, localanesthetic, antifungal agent, amoebicidal agent, trichomonocidal agent,analgesic agent, anti-arthritic agent, anti-asthmatic agent,anticoagulant agent, anticonvulsant agent, antidepressant agent,antidiabetic agent, antineoplastic agent, anti-psychotic agent,neuroleptic agent, antihypertensive agent, hypnotic agent, sedativeagent, anxiolytic energizer agent, antiparkinson agent, muscle relaxantagent, antimalarial agent, hormonal agent, contraceptive agent,sympathomimetic agent, hypoglycemic agent, antilipemic agent, ophthalmicagent, electrolytic agent, diagnostic agent, prokinetic agent, gastricacid secretion inhibitor agent, anti-ulcerant agent, anti-flatulentagent, anti-incontinence agent, and cardiovascular agent.
 17. A deviceaccording to claim 1, wherein the membrane comprises about 1 to 99weight percent of one or more cellulose esters, about 84 to 0.5 weightpercent of one or more poly(methacrylate) copolymer salts and about 15to 0.5 weight percent of one or more plasticizers.
 18. A deviceaccording to claim 1, wherein the cellulose ester is selected form thegroup consisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulose triacetateand combinations thereof.
 19. A device according to claim 1, wherein thepoly(methacrylate) copolymer salt is poly(ammonium methacrylate)copolymer.
 20. A device according to claim 1, wherein the plasticizer isselected from the group consisting of acetyl triethyl citrate, acetyltributyl citrate, triethyl citrate, acetylated monoglycerides, glycerol,poly(ethylene glycol), triacetin, propylene glycol, dibutyl phthalate,diethyl phthalate, dipropyl phthalate, dimethyl phthalate, dioctylphthalate, dibutyl sebacate, dimethyl sebacate, castor oil, glycerolmonostearate, and coconut oil.
 21. A device according to claim 1,wherein the first active agent is one of a biologically active agent,pharmacologically active agent, medicine, nutrient, food product,vitamin, insecticide, pesticide, herbicide, microbicide, algaecide,fungicide, grow regulating substance, parasiticide, sterilant, fertilitypromoter, biocide, rodenticide, disinfectant, plant growth promoter,preservative, fertility inhibitor, deodorant, catalysts, food supplementand cosmetic.
 22. The device of claim 1, wherein the layer furthercomprises at least one of an osmagent and an osmopolymer; the expandablecore further comprises at least one expandable hydrophilic polymer and,optionally, an osmagent.
 23. The device of claim 22, wherein themembrane comprises about 1 to 99 weight percent of one or more celluloseesters, about 84 to 0.5 weight percent of one or more poly(methacrylate)copolymer salts and about 15 to 0.5 weight percent of one or moreplasticizers.
 24. The device of claim 23, wherein the expandablehydrophilic polymer is one or more of hydroxypropyl methylcellulose,alkylcellulose, hydroxyalkylcellulose, poly(alkylene oxide), andcombinations thereof; and the at least one cellulose ester isindependently selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate and combinations thereof.
 25. The deviceof claim 23, wherein the at least one poly(methacrylate) copolymer saltis a poly(ammonium methacrylate) copolymer.
 26. The device of claim 2,wherein the layer further comprises at least one of an osmagent and anosmopolymer; the expandable core further comprises at least oneexpandable hydrophilic polymer and, optionally, an osmagent.
 27. Thedevice of claim 26, wherein the membrane comprises about 1 to 99 weightpercent of one or more cellulose esters, about 84 to 0.5 weight percentof one or more poly(methacrylate) copolymer salts and about 15 to 0.5weight percent of one or more plasticizers.
 28. The device of claim 27,wherein the expandable hydrophilic polymer is one or more ofhydroxypropyl methylcellulose, alkylcellulose, hydroxyalkylcellulose,poly(alkylene oxide), and combinations thereof; and the at least onecellulose ester is independently selected from the group consisting ofcellulose acylate, cellulose diacylate, cellulose triacylate, celluloseacetate, cellulose diacetate, cellulose triacetate and combinationsthereof.
 29. The device of claim 27, wherein the at least onepoly(methacrylate) copolymer salt is a poly(ammonium methacrylate)copolymer.
 30. A device for the controlled delivery of at least oneactive agent to an environment of use, wherein the device comprises: acore expandable in a fluid from the environment of use, the core beingapproximately centrally located in the device; a layer comprising atleast one first active agent, wherein the layer is in contact with andsurrounds the core; and a membrane in contact with and surrounding thelayer and comprising one or more cellulose esters, one or morepoly(methacrylate) copolymer salts and one or more plasticizers, whereinthe membrane permits delivery of the at least one active substancethrough a combination of diffusion and osmotic pumping.